Colorectal cancer is the second most commonly diagnosed cancer found in men and women in the United States. The vast majority of mortality of colorectal cancer patients is associated with formation of liver metastasis. According to American Cancer Society, the 5-year survival rate of colorectal cancer patients is 92% if the cancers have not metastasized. However, the 5-year survival rate drops to 7% once the cancer has metastasized to the liver. There is no effective therapy for metastatic colorectal cancer and prospects for cure remains poor. Resistance to apoptosis is a hallmark of metastatic human colorectal cancer. In humans, Fas is constitutively expressed in normal colon tissues, However, Fas expression is diminished in colorectal carcinoma, and complete loss of Fas expression and function is frequently observed in metastatic colorectal cancers. Induction of tumor cell apoptosis is the basis of many cancer therapies, including colorectal cancer therapies. Therefore, acquisition of resistance to apoptosis is one of the most significant challenges in colorectal cancer therapy. We have identified Interferon Regulatory Factor 8 (IRF8) as an essential regulator of apoptosis in human colorectal cancer cells. Furthermore, we observed that IRF8 expression is silenced in the vast majority of metastatic human colorectal cancer specimens through the IRF8 promoter DNA hypermethylation. In addition, ectopic expression of IRF8 restored the sensitivity of metastatic human colon carcinoma cells to Fas-mediated apoptosis in vitro and inhibited the growth of primary human colon carcinoma in a xenograft mouse model in vivo. Based on these novel observations, we hypothesize that IRF8 is a spontaneous colorectal cancer metastasis suppressor that functions through regulating tumor cell sensitivity to apoptosis, and metastatic colorectal cancer cells use the IRF8 promoter hypermethylation to silence IRF8 expression to acquire a metastatic phenotype. To test our hypothesis, we will pursue the following two specific aims: 1) to elucidate the molecular mechanisms underlying epigenetic regulation of IRF8 expression in human colon carcinoma cells; and 2) to determine the roles of IRF8 in spontaneous colon carcinoma metastasis in vivo, and to explore the potential of IRF8 mechanism-based therapies in suppression of colorectal carcinoma metastasis. Successful completion of this proposed research project will not only validate our hypothesis that IRF8 is a novel spontaneous metastasis suppressor but will also provide the molecular basis for the development of IRF8 mechanism-based therapies to target the deadly metastatic human colorectal cancer. PUBLIC HEALTH RELEVANCE: This proposed research project will elucidate the molecular mechanisms underlying epigenetic regulation of IRF8 expression in metastatic human colon cancer, and explore the potential of targeting IRF8 expression in combination with TRAIL therapy for the intervention of human colon carcinoma metastasis in vivo. Successful completion of the proposed research will provide a novel strategy for targeting the deadly metastatic human colorectal cancer.